More than ten million persons in the United States suffer from asthma and related inflammatory lung diseases. The numbers of persons with asthma is increasing both in the United States and worldwide. The morbidity associated with asthma makes asthma a major medical condition. Asthma is the most common chronic disease of childhood and the leading cause among chronic illnesses of school absences. Asthma in humans results in an estimated 27 million patient visits, 6 million lost workdays, and 90.5 million days of restricted activity per year. In addition to its morbidity, the mortality rate for asthma is growing worldwide. Additionally, asthma reactions are a growing problem for animals. In particular, the horse racing industry is affected by horses that suffer from asthmatic reactions.
Asthma is a lung disease characterized by a usually reversible airway obstruction, airway inflammation and increased airway responsiveness to stimuli. The airway obstruction in an asthma attack is thought to be due to the combination of bronchospasm of the smooth muscles of the bronchial tree, increased mucous section, edema of airway mucosa due to increased vascular permeability, cellular infiltration of the airway walls, and injury to airway epithelium.
Asthma may be triggered by a variety of causes such as allergic reactions, a secondary response to infections, industrial or occupational exposures, ingestion of certain chemicals or drugs, exercise, and vasculitis. Regardless of the trigger, many of the pathological features of asthma can be attributed to mast cell degranulation. Mast cells will degranulate in response to many conditions in addition to the classical IgE-antigen stimulation. Not wishing to be bound by the following theory, it is theorized that when the asthmatic, human or animal, inhales an allergenic substance, sensitized IgE antibodies trigger mast cell degranulation in the lung interstitium. The mast cell degranulation releases among other factors, histamine, bradykinin, and slow-reacting substance of anaphylaxis (SRS-A) which includes the leukotrienes C, D and E, prostaglandins including PGF.sub.2, PGF.sub.2.alpha., and PGD.sub.2, and thromboxane A.sub.2. The histamine then attaches to receptor sites in the larger bronchi, causing irritation, inflammation and edema. The SRS-A attaches to receptor sites in the smaller bronchi, causing edema and attracting prostaglandins, which enhance the effects of histamine in the lungs. With the help of the prostaglandins, histamine also stimulates excessive mucous secretion, further narrowing the bronchial lumen. When the asthmatic inhales, the narrowed bronchial lumen still expands slightly, allowing air to reach the alveoli. However, upon exertion to exhale, the increased thoracic pressure closes the bronchial lumen completely. Thus, in an asthma attack, air can enter, but not exit the lungs. Mucous then fills the lung bases, inhibiting alveolar ventilation. In an effort to compensate for lowered alveolar ventilation, blood is shunted to other alveoli. Without adequate compensation, hypoxia, and in extreme cases, respiratory acidosis may result.
In many cases, there are two phases to an allergic asthma attack, an early phase and a late phase which follows 4-6 hours after bronchial stimulation. The early phase includes the immediate inflammatory response including the reactions caused by the release of cellular mediators from mast cells. Late phase reactions develop over a period of hours and are characterized histologically by an early influx of polymorphonuclear leukocytes and fibrin deposition followed later by infiltration of eosinophils. Late phase reactions increase airway reactivity and lead to prolonged asthmatic exacerbations that may last from hours to days to months in some subjects. One of the residual effects of asthma reactions is this hyperresponsiveness of the airways to nonspecific stimuli.
The current treatments for asthma are not adequate and many have serious side effects. The general goals of drug therapy for asthma are prevention of bronchospasm and control of airway hyperreactivity or hyperresponsiveness, an indication of airway inflammation. One effective treatment is avoidance of all allergens that trigger an asthma attack. Though scrupulous housecleaning and air cleansing devices can lessen the exposures to allergens, it is very difficult to eliminate all exposures to allergens. Thus, most asthmatics are treated with pharmacological agents that have side effects.
Another common treatment regimen is administration of adrenergic agonists. These compounds mimic the physiological effects of the adrenal medullary hormones and neurotransmitters of the sympathetic nervous system. The ideal therapeutic target for asthma would be a compound that affected the .beta..sub.2 -receptors in the lung. .beta..sub.2 -receptors are found in the airway and their stimulation causes smooth muscle relaxation, increased chloride fluxes and reduced vascular permeability. These effects would be very useful in asthma therapy.
Many side effects result from treatment with adrenergic agonists because the adrenergic agonists are generally not selective for only the .beta..sub.2 -receptors, but also effect the .alpha.-receptors and .beta..sub.1 -receptors. .beta..sub.1 -receptors are found in the heart and adrenergic stimulation also leads to cardiac stimulation, which is a serious side effect of treatment with adrenergic agonists. Additionally, many of these compounds are rapidly metabolized and have very short half-lives, and thus are not effective therapy for asthma or hyperresponsiveness reactions. .beta..sub.2 -adrenergic agonists can be used for treatment of bronchospasm, but have no effect on airway inflammation or bronchial hyperreactivity. In fact, chronic use of .beta..sub.2 -adrenergic agents alone, by down regulation of .beta..sub.2 -receptors, may worsen bronchial hyperreactivity.
Asthma may also be treated with methylxanthines, such as theophylline. There is substantial variability in the absorbance and clearance of theophylline among animals. Even in individuals, theophylline clearance is effected by many physiological situations such as infection, antibiotic use, cigarette use and diet. The side effects of theophylline are nervousness, nausea, vomiting, anorexia, abdominal discomfort and headache. It is difficult to reach an effective drug level that provides asthma control without triggering side effects.
Corticosteroids are used to treat asthma by reducing the inflammatory component. Because the latephase asthmatic response is poorly responsive to bronchodilators, corticosteroids are used to treat late-phase and airway hyperreactivity reactions. These agents have tremendous toxicity in children, including adrenal suppression and reduced bone density and growth. In all age groups, corticosteroids have numerous side effects and complications which impact major organ systems. Use of oral corticosteroids must be closely monitored and its use curtailed or halted as soon as possible.
Cromolyn, another well known asthma therapeutic, acts by stabilizing mast cells and reducing or preventing release of the cellular mediators. Thus, cromolyn is effective in stopping or reducing both the early and late phases of asthma inflammatory reactions. Cromolyn is only effective in preventing the onset of an asthma reaction if given prior to an asthma attack. Once the asthma reaction has begun, the mediators have been released and treatment with cromolyn would do nothing to relieve the bronchoconstriction and hyperresponsiveness. Thus, asthma patients would have to take cromolyn continuously to prevent future asthma attacks that may or may not occur.
Thus, there is a long felt need for methods and compositions that are capable of inhibiting and stopping an asthma attack and its associated conditions, which are easily administered, and which do not have the side effects of currently used therapies. A simple and efficacious method of treatment would be through the inhalation route. If an anti-asthma agent could be given by an oral route, the many aspects of the pathology discussed above could be treated easily. The optimal dosage could be distributed in a form that the patient could self-administer at the onset of an attack or to stop hyperresponsiveness of the airways.